Neighbor effect on conformational spaces of alanine residue in azapeptides

• Published in: Heliyon 2024-06, Vol.10 (12), p.e33159, Article e33159
• Main Authors: Lee, Ho-Jin, Liu, Shi-Wei, Sulyok-Eiler, Máté, Harmat, Veronika, Farkas, Viktor, Bánóczi, Zoltán, El Khabchi, Mouna, Shawn Fan, Hua-Jun, Hirao, Kimihiko, Song, Jong-Won
• Format: Article
• Language: English
• Subjects: And Lcgau-BOP+LRD; Azapeptide; DFT functionals; Foldamer; LCgau-BOP; βI-turn; βII-turn
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2024.e33159

The conformational properties of Alanine (Ala) residue have been investigated to understand protein folding and develop force fields. In this work, we examined the neighbor effect on the conformational spaces of Ala residue using model azapeptides, Ac-Ala-azaGly-NHMe (3, AaG), and Ac-azaGly-Ala-NHMe (4, aGA1). Ramachandran energy maps were generated by scanning (φ, ψ) dihedral angles of the Ala residues in models with the fixed dihedral angles (φ = ±90°, ψ = ±0° or ±180°) of azaGly residue using LCgau-BOP and LCgau-BOP + LRD functionals in the gas and water phases. The integral-equation-formalism polarizable continuum model (IEF-PCM) and a solvation model density (SMD) were employed to mimic the solvation effect. The most favorable conformation of Ala residue in azapeptide models is found as the polyproline II (βP), inverse γ-turn (γ′), β-sheet (βS), right-handed helix (αR), or left-handed helix (αL) depending on the conformation of neighbor azaGly residue in isolated form. Solvation methods exhibit that the Ala residue favors the βP, δR, and αR conformations regardless of its position in azapeptides 3 and 4 in water. Azapeptide 5, Ac-azaGly-Ala-NH2 (aGA2), was synthesized to evaluate the theoretical results. The X-ray structure showed that azaGly residue adopts the polyproline II (βP) and Ala residue adopts the right-handed helical (αR) structure in aGA2. The conformational preferences of aGA2 and the dimer structure of aGA2 based on the X-ray structure were examined to assess the performance of DFT functionals. In addition, the local minima of azapeptide 6, Ac-Phe-azaGly-NH2 (FaG), were compared with the previous experimental results. SMD/LCgau-BOP + LRD methods agreed well with the reported experimental results. The results suggest the importance of weak dispersion interactions, neighbor effect, and solvent influence in the conformational preferences of Ala residue in model azapeptides. •Neighbor and solvent influence on Conformational Properties of Ala residue in azapeptides.•Ala residue could adopt polyproline II and alpha-helical/bridged conformation, depending on the position and solvent effect.•The X-ray crystal structure of Ac-azaGly-Ala-NH2 was solved.•SMD/LCgau-BOP + LRD calculation agrees with the experimental results.